Analgesic Effect Of Nitrous Oxide Research Articles

Analgesic effect of nitrous oxide during manual therapy after anterior cruciate ligament reconstruction: a study protocol for a randomized controlled trial

BackgroundMany patients during manual therapy after anterior ligament reconstruction will experience severe pain, which has a negative impact on their rehabilitation. However, there is rarely an analgesic method for these patients during rehabilitation. Nitrous oxide with rapid analgesic and sedative effects is often used to relieve pain in minor procedures. The purpose of this study is to determine whether or not nitrous oxide analgesia decreases pain compared to oxygen during manual therapy after anterior ligament reconstruction.Methods/designThis single-center, randomized, double-blind and controlled trial will recruit 120 patients. Patients ≥ 18 years old undergoing manual therapy after anterior ligament reconstruction (1 month post-operative) with acute pain (VAS ≥ 4) are included. The main exclusion criteria included the following: pulmonary embolism, intestinal obstruction, pneumothorax. Patients will be randomly allocated to the intervention group (A) and the control group (B) in a ratio of 1:1. Doctors, therapists, patients, and data collectors are all blind to the study. The manual therapy will be performed by therapists. Nurses who implemented the intervention handed the doctors envelopes containing the patients’ codes and allocation of A or B. Group A will receive a pre-prepared nitrous oxide/oxygen mixture plus conventional treatment (no analgesic) given as 30-min treatment sessions, once daily, and group B will receive oxygen plus conventional treatment (no analgesic) under the same conditions. Assessments will be taken 2 min before the intervention (T0), 5 min after the beginning of the intervention (T1), and 5 min after the intervention finished (T2). The primary outcome is pain score. Secondary outcomes include vital signs, side effects, joint range of motion, adjuvant analgesia need, therapist and patient satisfaction, and whether willing to receive the same gas again.Expected outcomesWe expect nitrous oxide inhalation to have a beneficial effect on the pain of patients who receive manual therapy after anterior ligament reconstruction.DiscussionIf this treatment appears beneficial, it could improve patients’ satisfaction and quality of life potentially and even be implemented widely in hospital and rehabilitation settings.Trial registrationClinicalTrials.gov identifier, ChiCTR2200061175 (Version 2.0 June 15, 2022), https://www.chictr.org.cn.

The use of inhaled nitrous oxide for analgesia in adult ED patients: a pilot study

BackgroundOligoanalgesia challenges emergency department (ED) health care providers and remains an area of patient dissatisfaction. Nitrous oxide (NO) is a safe, quick-acting, and well-tolerated sedative agent with analgesic and anxiolytic properties that make it ideal for ED use. ObjectivesWe seek to test the effectiveness of a self-administered and self-contained NO device as an analgesic agent in the ED and assess patient and staff satisfaction with this method. MethodsWe enrolled 85 patients 18 years and older in a prospective observational study of patients presenting to the ED with moderate to severe pain (≥30 mm on a 100-mm visual analog scale). Subjects received a mixture of 50% NO via a self-administered portable delivery device. Primary outcome was the reduction in baseline pain scores at 20, 40, and 60 minutes. Secondary outcomes were patient, nurse, and physician satisfaction as reported on a brief satisfaction questionnaire. ResultsThere was a significant reduction in mean pain scores from baseline to 20 minutes that was sustained through the 60-minute period. Most subjects (93%; 95% confidence interval [CI], 85%-97%) and nurses (97%; 95% CI, 90%-99%) reported that the NO delivery system was easy to use and were satisfied with the level of pain relief and would use NO in the future (82%; 95% CI, 73%-89%). Physicians and nurses were also satisfied with the analgesic effects of NO (82%; 95% CI, 73%-89%). ConclusionsThe portable NO device is an effective analgesia adjunct for ED patients presenting with painful conditions, and patients, ED nurses, and emergency physicians are satisfied with its use. Nitrous oxide coupled with a nurse-driven analgesia protocol may provide a novel solution for improvement in ED analgesia rates and overall patient satisfaction with ED pain management.

Analgesic and physiological effects in conscious sedation with different nitrous oxide concentrations.

Objectives: to study the physiological changes, as well as the psychosedative and analgesic effects of nitrous oxide, in experimental conditions. Study Design: 101 dental students volunteers participated in a single nitrous oxide sedation session without dental treatment. Signs and symptoms were registered during and after the procedure. Pulse rate and hemoglobin oxygen saturation were monitored at: 100 per cent O2, 30 per cent N2O, 50 per cent N2O and 5 minutes after 100 per cent O2. A Likert scale was used to evaluate pain perception. The analgesic effects of nitrous oxide were evaluated at: 30 per cent N2O, 50 per cent N2O, and five minutes postoperatively. Results: Pulse rate and hemoglobin oxygen saturation decreased significantly through all the procedure and after recovery. However, oxygen saturation recovered after the final oxygenation. Only 8.2% of subjects reported the pain stimulus as being quite annoying when they inhaled 30 per cent N2O, while this percentage was of 15.8 % when inhaling 50 per cent N2O, and of 32.7 % during the recovery period. The most common effects of nitrous oxide sedation were bright eyes (99%), voice change (98%) and smiling (91%). Most of the subjects reported tingling (98%) and relax (91.1%) Conclusions: nitrous oxide causes a significant decrease in heart rate and oxygen saturation, but always within safety limits. Maintaining an appropriate level of consciousness was confirmed as a feature in 50 per cent dose in this study. The analgesic effect of nitrous oxide was confirmed but a dose dependency could not be established. Key words:Nitrous oxide, conscious sedation, anxiolysis, safety, physiogical parameters, signs, symptoms, analgesia.

Evidence Is Lacking for Interventions Proposed to Prevent Unintended Awareness During General Anesthesia for Cesarean Delivery

To the Editor: We congratulate Drs. Robins and Lyons on their comprehensive and thought-provoking review of awareness during cesarean delivery under general anesthesia with subsequent explicit recall.1 Historically, patients undergoing cesarean delivery with general anesthesia have been considered to be at greater risk for awareness, but recent research suggests that, with modern anesthetic techniques, the risk may be comparable to that of the general surgical patient.2 We have concerns regarding some of the techniques proposed to decrease the likelihood of awareness in the setting of cesarean delivery1 and would welcome clarification. Because processed electroencephalograph (EEG) monitors have not been sufficiently assessed in pregnant patients, it may be imprudent to assume that they are informative in this patient population. Furthermore, none of the patients in the B-Aware study who had “definite” awareness had a cesarean delivery3; therefore, evidence for the utility of processed EEG monitors in pregnant patients cannot be inferred from this study. In general, there is equipoise regarding the ability of processed EEG monitoring to decrease awareness in any surgical population, particularly when a potent inhaled anesthetic is administered.4,5 For women undergoing cesarean delivery with propofol-based total IV anesthesia, the case for using a processed EEG monitor may be more compelling. The further recommendation to administer a high concentration of nitrous oxide is surprising because current processed EEG monitors measure nitrous oxide's anesthetic effects poorly. The combination of nitrous oxide and processed EEG monitoring may therefore prompt unnecessarily deep anesthesia with consequences for the neonate that might include neurotoxicity.6 Moreover, the suggestion that because “the effect of nitrous oxide on memory is uncertain, prudent advice would be to regard the target MAC as that of the volatile alone” compounds this possibility. Whereas nitrous oxide and volatile anesthetics are additive for producing patient immobility, they may be antagonistic for producing analgesia.7 Accumulating preclinical and clinical evidence suggests that GABAergic general anesthetics attenuate the analgesic effects of nitrous oxide. On the strength of these data, a patient may derive more analgesic benefit from a sole potent volatile anesthetic than from its combination with nitrous oxide.7 This is likely to be even more significant when the administration of opioids is delayed as occurs during cesarean delivery.7 Therefore, it seems sensible to avoid nitrous oxide in this context, especially because any pharmacokinetic benefit over newer volatile anesthetics is minimal, and any hypothetical decrease in the rate of awareness has not been substantiated in clinical trials. Robert D. Sanders, BSc, MBBS, FRCA Departments of Leucocyte Biology and Anaesthetics Intensive Care and Pain Medicine Imperial College London Chelsea and Westminster Hospital London, UK [email protected] Michael S. Avidan, MBBCh, FCASA Department of Anesthesiology Washington University in St. Louis St. Louis, Missouri

Nociceptin receptor antagonist JTC-801 inhibits nitrous oxide-induced analgesia in mice

The mechanism of the analgesic effect of nitrous oxide (N(2)O) has not been completely clarified. Although we have reported that the analgesic effect of N(2)O was significantly decreased in nociceptin-orphanin FQ (N/OFQ) receptor (NOP)-deficient mice, the effect of nociceptin receptor antagonists on N(2)O-induced analgesia has not been reported. In this investigation, we examined the effect of the NOP antagonist JTC-801 on N(2)O-induced analgesia in 129Sv mice by the writhing test and tail flick test, and demonstrated that the analgesic effect of N(2)O was suppressed by the intraperitoneal administration of JTC-801.

Nitrous oxide and the inhibitory synaptic transmission in rat dorsal horn neurons

The analgesic effect of nitrous oxide (N 2O) is thought to depend on noradrenaline release in the spinal cord following activation of descending inhibitory neurons. In addition to this indirect facilitation of inhibition in the spinal cord, we previously showed direct inhibition of glutamate receptors in dorsal horn neurons by N 2O. Since general anesthetics could possibly affect excitatory and/or inhibitory components of synaptic transmission, we sought to evaluate the direct effect of N 2O on inhibitory transmission in spinal cord neurons. Using whole-cell patch-clamp recording from rat transversal spinal cord slices, we investigated the actions of 50% N 2O and 0.5% isoflurane (both 0.3 rat MAC; minimum alveolar concentration) on exogenously applied γ-aminobutyric acid (GABA)- and glycine-induced currents in rat dorsal horn lamina II neurons. The amplitudes and integrated areas of GABA- and glycine-induced currents were not significantly affected by N 2O, but were increased in the presence of isoflurane. N 2O did not affect the amplitude, frequency or decay time probability distribution of either GABA or glycine receptor-mediated miniature postsynaptic currents. We further sought to determine the effect of N 2O on focal stimulation-evoked synaptic currents mediated by GABA and glycine receptors, and found no effect in the majority of neurons. These and other findings suggest that N 2O has a discrete action in the spinal cord, distinct from the effects of the volatile anesthetics, consisting of inhibition of excitation in SG neurons through an action on ionotropic glutamatergic receptors and potentiation of inhibition through the descending noradrenergic system.

Comparison of the sedative, cognitive, and analgesic effects of nitrous oxide, sevoflurane, and ethanol

Anaesthetics which work by different mechanisms may have different patterns of effect. Measurement of these patterns thus may elucidate their mechanisms of action and allow therapeutic choices between the agents. We compared the effects of ethanol (approximately 80 mg per 100 ml), and different end-tidal concentrations of nitrous oxide (15% and 25%) and sevoflurane (0.3% and 0.5%) in volunteers. We measured speed and accuracy in psychomotor tests, reaction time and memory, touch and pain sensitivity to von Frey filaments, and subjective mood for a range of descriptors. All treatments caused the same degree of overall abnormal feelings, but sevoflurane caused more obtunding (subjective drowsiness, slow reaction times, and loss of memory function) and nitrous oxide was more analgesic. Ethanol caused a marked feeling of drunkenness, but little drowsiness or analgesia. In the same volunteer subjects, direct comparison of sub-anaesthetic doses of these agents showed a clear and characteristic pattern of effects. These support the possible mechanisms for these disparate agents and may help choose appropriate agents for specific desired anaesthetic outcomes such as sedation or analgesia.

A prospective randomized crossover study of the preemptive analgesic effect of nitrous oxide in oral surgery

Objective Preliminary animal data has shown that nitrous oxide has a preemptive analgesic effect on postoperative pain. Whether a similar effect occurs in humans is not established. In this prospective randomized crossover study, we investigated the effect of preincisional versus postincisional nitrous oxide on postoperative oral surgical pain. Study design The trial was a crossover study where 36 patients had each of their symmetrical impacted mandibular third molars randomly scheduled for removal in 2 sessions. Each of the 36 patients acted as his or her own control; one side of the jaw was allocated randomly to receive nitrous oxide preoperatively (pretreated side) and the other side postoperatively (posttreated side). The pretreated side received 50% nitrous oxide preoperatively for 20 minutes and 100% oxygen postoperatively for 20 minutes as placebo. The posttreated side received 100% oxygen preoperatively for 20 minutes and 50% nitrous oxide postoperatively for 20 minutes. The difference in postoperative pain between the pretreated and posttreated sides was assessed by 4 primary end-points: pain intensity as measured by a 100-mm visual analog scale (VAS) hourly for 8 hours, time to first analgesic, total analgesic consumption during the first 48 hours, and a 5-point categorical patient global assessment scale (0 = poor, 1 = fair, 2 = good, 3 = very good, and 4 = excellent). Results The VAS scores did not differ between the 2 sides at any time ( P = .50): neither did the time to first analgesic ( P = .8), amount of total analgesic consumption ( P = .77), and patient's global assessment differ ( P = .63). Conclusion Our results do not support the preliminary animal data that nitrous oxide has a preemptive analgesic effect for postoperative pain. 50% nitrous oxide administered preoperatively for 20 minutes has no preemptive analgesic effect on postextraction pain.

Dexmedetomidine enhances analgesic action of nitrous oxide: mechanisms of action.

Nitrous oxide and dexmedetomidine are thought to mediate analgesia (antinociception in a noncommunicative organism) via alpha 2B- and alpha 2A-adrenergic receptor subtypes within the spinal cord, respectively. Nitrous oxide and dexmedetomidine exert diametrically opposite effects on neuronal activity within the locus ceruleus, a pivotal site for modulation of analgesia. Because of these differences, the authors explored whether the two analgesics in combination would provide satisfactory analgesia. The analgesic effects of nitrous oxide and dexmedetomidine given both intraperitoneally and intrathecally were evaluated using the tail-flick latency test in rats. For investigation of the interaction, rats were pretreated with dexmedetomidine, either intraperitoneally or intrathecally, immediately before nitrous oxide exposure such that peak antinociceptive effects of each drug coincided. For assessment of the effect on tolerance, dexmedetomidine was administered as tolerance to nitrous oxide developed. Expression of c-Fos was used to assess neuronal activity in the locus ceruleus. Nitrous oxide and dexmedetomidine increased tail-flick latency with an ED50 (mean +/- SEM) of 55.0 +/- 2.2% atm for nitrous oxide, 27.6 +/- 5.1 for microg/kg intraperitoneal dexmedetomidine, and 2.9 +/- 0.1 microg for intrathecal dexmedetomidine. Combinations of systemically administered dexmedetomidine and nitrous oxide produced an additive analgesic interaction; however, neuraxially administered dexmedetomidine interacted synergistically with nitrous oxide. Tolerance to nitrous oxide was reversed by coadministration of dexmedetomidine. Prazosin, the alpha 1-/alpha 2B-adrenoceptor antagonist, attenuated the analgesic effect of nitrous oxide and prevented dexmedetomidine-induced reversal of tolerance to nitrous oxide. Nitrous oxide-induced increase of neuronal activity in the locus ceruleus was reversed by dexmedetomidine. The synergistic analgesic interaction between nitrous oxide and dexmedetomidine within the spinal cord is obscured by a supraspinal antagonism when dexmedetomidine is administered systemically in the pretolerant state. After tolerance to nitrous oxide develops, supraspinal functional antagonism no longer obtains exposing the synergistic action at the level of the spinal cord, which expresses itself as a reversal of the tolerant state. The authors speculate that the addition of dexmedetomidine to nitrous oxide is likely to provide enhanced and more durable analgesia in settings in which nitrous oxide is currently used alone (e.g., labor and dental surgery).

Nitrous oxide lacks the antinociceptive effect on the tail flick test in newborn rats.

Nitrous oxide (N(2)O) is commonly used for pediatric anesthesia under the assumption that it produces a similar analgesic response to that seen in adults. We examined the antinociceptive effect of 75% N(2)O on tail flick latency response in newborn rats at postnatal Day 1 (PD 1), PD 8, PD 15, PD 22, and PD 29. Up to PD 15, rats showed no analgesic effect to N(2)O. By PD 29, rats exhibited a comparable analgesic effect to that seen in adult animals. These data are consistent with the fact that the descending noradrenergic neurons, which are required for the analgesic action of N(2)O, are not anatomically or functionally developed at birth and take more than three weeks to fully develop in rats. The present study indicates that rats below 3 wk old lack an antinociceptive effect to nitrous oxide by using the tail flick test. Because a 3-wk-old rat is comparable in neurological development with the toddler stage in humans, we may anticipate that patients below this age may not experience the usual analgesic effect of nitrous oxide.

In Memory of Shih-hsun Ngai, M.D. (1920–1999)

SHIH-HSU N Ngai, a distinguished anesthesiologist and pharmacologist and former Editor of ANESTHESIOLOGY, died of lung cancer on July 8, 1999, shortly before his 79th birthday. He was born in Wuchang, China, on September 15, 1920, the youngest and eighth child of a high school teacher. A graduate of China’s Central University Medical School, he spent almost his entire professional career at Columbia University’s Department of Anesthesiology after winning a competitive government fellowship to study anesthesiology abroad. At Columbia, he rose to be Professor of Anesthesiology in 1965 and of Pharmacology in 1974. He spent 2 yr in the US Army (1955–1957) and chaired the Department of Anesthesiology from 1969–1973. He was a distinguished clinician, scientist, teacher, and mentor. FIGUREAs a clinician, Dr. Ngai was knowledgeable, compassionate, and highly skilled. He was greatly regarded as a preceptor to residents because, while teaching them to provide anesthesia, he also made them think about their every action.Dr. Ngai began his research even as a resident, doing pioneering studies on central nervous system control of respiration with Dr. S. C. Wang, the renowned physiologist, that are classics. Later, at Columbia and with collaborators elsewhere, he studied the interactions of biogenic amines with general anesthetics. He also studied narcotics, narcotic antagonists, and the participation of opioid receptors in anesthetic-induced analgesia. His work always seemed a step ahead of his time. An article in Science in 1976 about the analgesic effect of nitrous oxide stimulated controversy, which persists to now. Seven of his nine research fellows remain in the academic practice of anesthesiology, a remarkable record. Upon his retirement in 1988 the Shih-hsun Ngai Research Fellowship was established to honor his accomplishments.For many years, Dr. Ngai was affiliated with the biomedical and anesthesiology communities of Taiwan. He was Visiting Professor at National Taiwan University in 1990, the Tri-service Hospital in 1992, and the Veteran’s General Hospital in 1994. During these visits, he upgraded the practice, teaching, and research of anesthesiology in Taiwan. He also was a founding member of the National Health Research Institute, which is similar to the National Institutes of Health in the United States.Perhaps only his closest associates knew that he had an uncanny mastery of scientific writing and English. He helped many at Columbia University and in Taiwan with grant applications and manuscripts, and edited all accepted papers for the Chinese anesthesiology journal Acta Anaesthesiologica Sinica . Dr. Ngai was a man with great integrity in both his personal and professional lives. He had a passionate curiosity informed by keen observation. His high standards, unwavering sense of fairness, and commitment to do the right thing, along with a quiet humor, touched everyone around him. Prestigious honors included the Commonwealth Fellowship (1964), election to the Academia Sinica (Taiwan, 1972), the National Research Council Anesthesia Committee (1961–1970), and several National Institutes of Health Study Sections (1962–1982). Elected to the editorial board of ANESTHESIOLOGY, he served for 10 years (1967–1977), having been asked to continue beyond the normal term because of his special contributions.Dr. Ngai is survived by his wife, Dr. Hsueh Hwa Wang, Professor Emeritus of Pharmacology of Columbia University; two daughters, Mae, Assistant Professor of History at the University of Chicago; Janet, a physical therapist in Massies Mill, Virginia; a son, John, Associate Professor of Neurobiology and Head of the Neurobiology Graduate Program at the University of California at Berkeley; five grandchildren; and memories of a joyous 50th wedding anniversary family reunion on Christmas, 1998.He is profoundly missed, but his memory lives in the hearts of his friends.

Effects of naloxone on nitrous oxide actions in healthy volunteers

A number of studies have examined the effects of naloxone on nitrous oxide-induced analgesia with conflicting results. In the present study the effects of a relatively high dose of naloxone was examined to determine its effects on nitrous oxide-induced analgesia, as well as on the subjective and psychomotor effects of nitrous oxide. Fourteen subjects participated in a four-session crossover trial in which they received intravenous injections of either saline or 30mg/70kg naloxone 10min into a 35min period in which they were inhaling either 100% oxygen or 30% nitrous oxide in oxygen. Ten minutes after the naloxone administration, subjects were tested on the cold pressor test. Mood and psychomotor performance were also assessed before, during and after the inhalation period. Subjects reported higher pain ratings after the naloxone injection than the saline injection, but there was no evidence of naloxone reversing the analgesic effects of nitrous oxide. Similarly while naloxone also affected mood and impaired psychomotor performance, there was no evidence of naloxone reversing the effect of nitrous oxide on these measures. The results of this study call into question the role of the opioidergic system in mediating various effects of nitrous oxide in humans.

The Effects of Subanesthetic Concentrations of Sevoflurane and Nitrous Oxide, Alone and in Combination, on Analgesia, Mood, and Psychomotor Performance in Healthy Volunteers

We studied the effects of subanesthetic concentrations of sevoflurane and nitrous oxide, alone and in combination, on analgesia, mood, and psychomotor performance in human volunteers. We hypothesized that nitrous oxide and sevoflurane would produce both opposing and potentiating effects within the same study. Over the course of three sessions, 20 subjects inhaled 0%, 0.2%, or 0.4% end-tidal sevoflurane for a 68-min period that was divided into four 17-min blocks. During either the second or fourth block, 30% end-tidal nitrous oxide was added to the concentration of sevoflurane being inhaled. Pain response, psychomotor performance, and mood were evaluated during the second and fourth blocks. Pain ratings were higher when sevoflurane and nitrous oxide were administered together than when nitrous oxide was administered alone, which indicates that sevoflurane attenuated the analgesic effects of nitrous oxide. Sevoflurane increased self-reported ratings of sleepiness, and the addition of nitrous oxide decreased these ratings. Nitrous oxide potentiated psychomotor impairment that was induced by sevoflurane. The combination of sevoflurane and nitrous oxide produced both opposing and potentiating effects within the same study. The results suggest that nitrous oxide and sevoflurane may act through different neurochemical mechanisms on some end points, such as analgesia and sleepiness. Healthy volunteers inhaled subanesthetic concentrations of sevoflurane and nitrous oxide. Sevoflurane made nitrous oxide less effective as an analgesic, and nitrous oxide made sevoflurane less effective as a sedative. The two drugs may work at cross purposes on different end points of anesthesia.

Neural basis of inhalant abuse

It should be apparent from this review that far less is known about the neural basis for inhalant abuse than for other forms of drug abuse. This reflects a lack of research interest in this area (Balster, 1997). Indeed, conclusions are difficult to draw. In the case of the volatile alkyl nitrites, the most reasonable hypothesis at this time is that the cellular basis for their abuse resides in their actions on smooth muscles to produce vasodilation and relaxation, however, direct effects on the brain cannot be ruled out. Although there is some evidence that analgesic effects of nitrous oxide may involve opiate systems, even this conclusion is controversial. There is no evidence that opiate systems play a role in nitrous oxide intoxication or reinforcement. The mechanisms for these effects are unknown. They may reflect the same actions on lipid membranes or on hydrophobic sites on unspecified proteins that have been proposed as mechanisms for nitrous oxide anesthesia. In the case of the volatile solvents, fuels and anesthetics we are faced with a wide variety of specific chemicals which may produce different profiles of pharmacological effects. There is evidence that the prototypic abused solvents toluene and trichloroethane produce acute effects similar to subanesthetic concentrations of general anesthetics, as well as to the effects of classical CNS depressant drugs, such as alcohol and the barbiturates. For the anesthetics, evidence suggests that enhancement of GABAergic inhibition may be an important cellular target for their acute effects, just as it is for alcohol and other depressant drugs. For toluene, as with alcohol, recent evidence suggests a possible role for inhibition of glutamatergic neurotransmission involving NMDA receptors. Toluene has also been shown to have some dopaminergic effects which may be important to its abuse. As for the large number of other abused vapors, practically no information can be found on their cellular actions, and certainly not on actions that may be relevant to their abuse. This entire area would seem an important direction for future research.

Opiate receptors in the periaqueductal gray mediate analgesic effect of nitrous oxide in rats

The site of action and the pathways which are activated by nitrous oxide (N2O) to produce an analgesic effect are not well defined. Experiments were designed to determine whether N2O produces analgesia by activating opiate receptors or α2-adrenoceptors in periaqueductal gray. The analgesic effect of N2O was determined using the tail flick response to noxious radiant heat in lightly anesthetized rats. Different antagonists were bilaterally microinjected into ventrolateral periaqueductal gray to determine whether the analgesic effect produced by N2O was reversed. The increase in the tail flick latencies produced by N2O was reversed by bilateral microinjection into the ventrolateral part of periaqueductal gray with the opiate receptor antagonist naloxone 2.5 μg/0.5 μl, but not with the α2-adrenoceptors antagonist yohimbine 1.5 μg/0.5 μl. These results indicate that the N2O analgesic effect is mediated by activation of opiate receptors, but not α2-adrenoceptors, in the periaqueductal gray. Combined with the previous experiments that the N2O analgesic effect is reversed by intrathecal injection of an α2-adrenoceptor antagonist but not by an opiate receptor antagonist, it seems likely that N2O causes activation of the opiate receptors in the periaqueductal gray, which in turn activate the noradrenergic descending pathways to the spinal cord to produce the analgesic effect.

Nitrous oxide induces preemptive analgesia in the rat that is antagonized by halothane.

Noxious stimulation-induced sensitization of the central nervous system has been proposed as a key element in the development of subsequent protracted pain. Accordingly, the authors used the formalin model of pain to test the hypothesis that general anesthesia can produce preemptive analgesia and thereby interfere with noxious stimulation-induced central sensitization. Rats received 0.9% or 1.8% halothane, 30% or 75% nitrous oxide (N2O), or 75% N2O plus 0.9% halothane (n = 4 or 5 per group). Control rats (n = 5) received only 100% oxygen. Fifteen minutes after the induction of anesthesia, formalin was injected subcutaneously into a hind paw of each rat, and anesthesia was maintained for 5 more min. Because the behavioral pain response to formalin (i.e., flinching of the injected paw) is biphasic, these treatment groups were anesthetized only during phase 1 (acute phase). Another group (n = 5) received 75% N2O only during phase 2 (delayed phase). Reversibility of the N2O effect was tested by the administration of naloxone before phase 1 or naltrexone during phase 2 (n = 5 per group). Finally, additional rats anesthetized as described above (n = 4 or 5 per group) underwent tail-flick testing during anesthesia. All anesthetics reduced phase 1 pain behavior, but only N2O produced antinociception on tail-flick testing. Thirty percent and 75% N2O, administered during phase 1, suppressed phase 2 flinching 29% and 49%, respectively, whereas nitrous oxide administered after phase 1 did not suppress phase 2 pain behavior. This effect of nitrous oxide was reversed by an opioid antagonist given during phase 1 but not phase 2. Halothane administered during phase 1 had no effect on phase 2 flinching, and it antagonized the effect of 75% N2O. Nitrous oxide induces dose-dependent preemptive analgesia in this model that is reversed partially by naloxone, thus suggesting the involvement of endogenous opioids in this action. In contrast, halothane has no preemptive analgesic properties and even antagonizes the analgesic effect of nitrous oxide. Hence, the hypnotic potency of an anesthetic is a poor indication of its preemptive analgesic potential.

顔面部の触覚・痛覚に及ぼす笑気吸入の影響

This study was undertaken to examine the effects of nitrous oxide (N_2O) inhalation on tactile and pain thresholds measured on the buccal skin of human. The subjects consisted of 28 healthy men aged 23-28 years with a mean of 24.7 years and weighed 50-90kg with a mean of 65.1kg. The subjects were divided into four groups according to which of four gases they inspired, 30%, 50%, 65% N_2O mixed with oxygen, and 100% oxygen as a control. Nylon threads with three different diameters and lengths and analgesiometers were used for measurements of tactile and pain thresholds, respectively. The subjects were instructed to recline on a dental chair comfortably in the supine position. After ten minutes' rest, measurements were started three times each at 10-minute intervals during breathing room air as a control, during inhaling the respective concentration of N_2O and during withdrawal period. The data calculated as the maximum possible effect were statistically compared with those of the control group. The results obtained were as follows. 1) Thresholds of tactile sensibilities on the buccal region were increased to 34%, 34% and 17% up from the control in 30%, 50% and 65% N_2O gpoups, respectively, but there were no significant differnces from the control value. 2) Thresholds of pain sensibilities on the buccal region showed significant increases from control value and 100% O_2 group (control group) during N_2O inhalation period in N_2O groups except at 20 and 30 minutes' point in 30% N_2O inhalation. 3) In physiological variables, there was no significant difference from the control value and 100% O_2 group (control group) such as heart rates, blood pressure, respiratory rate and oxyhemoglobin in every N_2O administration. These results indicate that analgesic effects of nitrous oxide at the buccal region in human face exist even in 30% N_2O and these effects are enhanced in accordance with that dose although there are no effects on tactile sensibilities and cardio-pulmonary function.

SOMATOSENSORY AND AUDITORY EVOKED RESPONSES RECORDED SIMULTANEOUSLY: DIFFERENTIAL EFFECTS OF NITROUS OXIDE AND TSOFLURANE

Auditory (AER) and somatosensory evoked responses (SSER) were recorded simultaneously in eight patients under anaesthesia before surgery. We studied the effects of equi-MAC end-expiratory concentrations of isoflurane (0.65-0.75%) and nitrous oxide (60-65%). The anaesthetics were changed at random in three consecutive 10-min periods so that each patient received both drugs. From the AER recorded from the vertex and inion, Pa and Nb latency and amplitude were measured. N13, P20 latency and N13 amplitude were measured from SSER recordings from the neck and P15, N20, P25, N35, P45 latency and P15-N20, N20-P25, P25-N35 and N35-P45 amplitude from the scalp over the hand area of the sensory cortex. Compared with nitrous oxide, isoflurane significantly increased the latencies of the AER waves Pa (P = 0.02) and Nb (P = 0.02), and the SSER waves N20 (P = 0.001) and P25 (P = 0.04). We were unable to demonstrate significant differences in Pa and Nb amplitude between isoflurane and nitrous oxide that we had seen previously. However, the amplitude of the SSER wave N20 was reduced significantly by nitrous oxide compared with isoflurane (P = 0.0004). This wave (N20) is thought to emanate from the thalamo-cortical radiations, and our findings may be explained by an analgesic effect of nitrous oxide mediated by endogenous opioids.

Clinical use of opioid antagonists

The preparation of normorphine and norcodeine by von Braun in 1914 made practical the synthesis of a series of derivatives differing from the parent compounds only by the radical substituted on the nitrogen atom. In 1915, Pohl investigated N-allylnorcodeine on the assumption that the addition of an allyl group conferred respiratory stimulant properties on drugs. Although this tenet proved to be incorrect, Pohl did succeed in showing that N-allylnorcodeine would prevent or abolish the respiratory depressant effects of morphine and diacetylmorphine (diamorphine BP) (Pohl, 1915). These observations suffered a fate similar to that of Humphrey Davey's finding of the potential analgesic effect of nitrous oxide--total neglect. It was not until Unna (1943) described the morphine antagonistic properties of N-allylnormorphine (nalorphine), following its synthesis by Weijland and Erikson two years earlier (Weijland and Erikson, 1942), that interest was aroused. It was also shown (Hart and McCawley, 1944) that the substitution in the opiate molecule of N-methyl by N-allyl produced a compound in which the respiratory depressant effect was eliminated, equivalent analgesic effect was maintained, but the action on the gastrointestinal tract was altered. They also showed that the substituted compound had a marked antagonistic effect upon the parent compound. Although these observations suggested that nalorphine could be valuable in the treatment of opiate intox!cation, this potential was not realized until 1951 by Eckenhoff who described its use in the treatment of opiate overdosage in man (Eckenhoff et al, 1951). The precipitation of abstinence by nalorphine and its production of dysphoric effects in man led Isbell and Fraser (1950) to suggest that it might be an effective analgesic with an abuse potential lower than that of morphine and other opiates. Even though these analgesic effects were described shortly after by Lasagna and Beecher (1954) it was as an opiate antagonist that nalorphine achieved clinical acceptance. The major factors limiting its usefulness, however, were the intense dysphoria that was observed at therapeutic doses (Telford et al, 1961) and the physical dependence that developed after sustained use (Martin and Gorodetsky, 1965). Nevertheless, nalorphine was used for a long period as an antidote for opiate overdose. 'It is a tricky drug to use. Too little will not reverse morphine effects; too

A pharmacological overview of opioid mechanisms mediating analgesia and hyperalgesia

We present a review of the opioid mechanism of analgesia and hyperalgesia and attempt to integrate some of the most recent findings in neuro-anatomy, neuro-physiology and neuropharmacology that indicate the presence of two distinct opioid systems; the one analgesic and the other hyperalgesic. The initial finding of a paradoxical effect of naloxone in which it was able to enhance the analgesic effects of nitrous oxide under certain circumstances led us to postulate the existence of such antagonistic opioid systems which appear to be important in the perception. The review details the further experimental evidence that has subsequently emerged to support our original hypothesis. This includes a hypothesis developed by other workers (viz. diffuse noxious inhibitory control system) which has attempted to explain the analgesic effects of naloxone. Recent anatomical evidence locating the hyperalgesic system in the medullary pontine region is given.